Method for preparing 1,3-dicarbonyl compound based on metal hydride/palladium compound system

ABSTRACT

Disclosed is a method for preparing a 1,3-dicarbonyl compound based on a metal hydride/palladium compound system. The method includes the following steps: suspending a palladium compound and a metal hydride in a solvent under the protection of nitrogen, then adding an electron-deficient olefin compound, reacting same at 0° C.-100° C. for 0.3 to 10 hours, then adding a saturated ammonium chloride aqueous solution to stop the reaction, and then subjecting same to extraction, evaporation until dryness, and column chromatography purification to obtain the 1,3-dicarbonyl compound. The hydride and palladium compound catalysts used by the present invention are reagents easily obtained in a laboratory. Compared to a common hydrogen hydrogenation method, the method is easier to operate, and has a higher safety, mild conditions, and a high reaction yield.

This application is a Continuation Application of PCT/CN2018/106060,filed on Sep. 17, 2018, which is incorporated by reference for allpurposes as if fully set forth herein.

TECHNICAL FIELD

The present invention relates to the technical field of organicsynthesis, and particularly relates to the application of a metalhydride/palladium compound system in preparing 1,3-dicarbonyl compoundswith a Michael-Dieckmann cascade reaction of an electron-deficientolefinic compound, and more particularly relates to a method ofpreparing a 1,3-dicarbonyl compound based on metal hydride/palladiumcompound system.

BACKGROUND TECHNIQUE

Sodium hydride is a strong base often used in the laboratory andindustry. For a long time, there have been few reports about its use asa reducing agent. Existing technologies using sodium hydride require alarge excess of sodium hydride (more than 5 equivalents), and at least 2equivalents of sodium iodide are required as accelerators.

Reduction of electron-deficient olefinic compounds is a common chemicalconversion to produce corresponding saturated carbonyl compounds. Thistype of reaction generally uses hydrogen/palladium-carbon conditions forreduction; in addition, some hydrogen negative reagents would reduce theelectron-deficient double bond, such as [(Ph₃P)CuH]₆ (Stryker reagent),R₃SiH, Hantzsch esters, etc. However, these reactions are dangerous moreor less, such as explosive hydrogen, expensive reagents, the lack ofatomic economy, and more waste to be processed after the reaction, suchas [(Ph₃P)CuH]₆ (Stryker reagent), R₃SiH, Hantzsch ester, etc.

SUMMARY OF THE INVENTION Technical Problems

The technical problem to be solved by the present invention is toprovide the application of a metal hydride/palladium compound system,which is in preparation of 1,3-dicarbonyl compound 3 with aMichael-Dieckmann cascade reaction of electron-deficient olefiniccompound 1 with ortho ester group substituent.

Technical Solutions

The present invention adopts the following technical solutions:

A method of preparing 1,3-dicarbonyl compound based on metalhydride/palladium compound system comprising: under the protection ofnitrogen, stirring suspended palladium compound and metal hydride are ina solvent, then add the electron-deficient olefin compound, the reactionis performed at 0° C. to 100° C. for 0.3 to 10 hours, to obtain the1,3-dicarbonyl compound.

In the Michael-Dieckmann reaction of the present invention, the metalhydride is used as a reducing agent, palladium and its salts are used asa catalyst, and the electron-deficient olefin compound is a substrate toreact in solvent to obtain the cascade reaction product 1,3-dicarbonylcompound.

In the present invention, the metal hydride is sodium hydride, lithiumhydride, potassium hydride or calcium hydride; preferably, sodiumhydride or lithium hydride; more preferably, sodium hydride.

In the present invention, the palladium compound is palladium chloride,palladium acetate, Pd₂(dba)₃, Pd(TFA)₂, [(η³-C₃H₅)PdCl]₂, Pd(dppp)Cl₂,Pd(C₆H₅CN)₂Cl₂, Pd(OH)₂; preferably, palladium chloride and palladiumacetate; and more preferably, palladium chloride.

Beneficial Effects of the Present Invention Beneficial Effects

The Michael-Dieckmann cascade reaction with sodium hydride/palladium hasthe following advantages: 1) Comparing with the other reducing agents,sodium hydride is cheaper; compared with hydrogen reduction, the sodiumhydride method is safer. 2) Sodium hydride has a small molecular weightand simple composition, and the amount used in the reaction is small, sousing sodium hydride as a reducing agent is an atomic economic method;by-products include harmless sodium salt, and no other waste isgenerated. 3) Sodium hydride and palladium catalysts are reagentscommonly used in the laboratory, which is very convenient to use. 4)Compared with Stryker reagent, the combined price of sodiumhydride/palladium is much cheaper, and the palladium reagent can berecycled, so it is more suitable for laboratory and industrialapplications.

The electron-deficient olefin compound has the following structure:

R is aryl, alkyl, alkoxy, amino group etc.

In the present invention, a molar ratio of the palladium compound:themetal hydride:the electron-deficient olefin compound is (0.01 to 1):(1to 5):1; preferably, the molar ratio of the palladium compound:the metalhydride:the electron-deficient olefin compound is (0.05 to 0.15):(1 to3):1; more preferably, the molar ratio of the palladium compound:themetal hydridea:the electron-deficient olefin compound is 0.1:(1.5 to2.5):1; and most preferably, the molar ratio of the palladiumcompound:the metal hydride:the electron-deficient olefin compound is0.1:2:1.

The technical solution above can be expressed as follows:

Wherein R is aryl group, alkyl group, alkoxy group, amino group, etc.; Mis a metal, such as lithium, sodium, potassium, or calcium, etc.

The conversion from compound 1 to compound 3 in the convention art canbe completed in steps, for example, first reducing the double bond withhydrogen, and then treating with alkali to obtain 3; it can also becompleted in one pot reaction using Stryker reagent, i.e., conducting aMichael type conjugate reduction reaction of the double bond in compound1 and a Dieckmann reaction to obtain compound 3. In this process, thestepwise reaction operation is complicated, the cost is high, and thewaste generated is large. Although the one-pot reaction is simple, theStryker reagent is very expensive (1 g>500 Chinese yuan). Therefore, theoverall cost is actually higher than the step-by-step method.

In the above technical solution, after the reduction reaction, addsaturated ammonium chloride aqueous solution to stop the reaction, andthen the product is subjected extraction, drying, rotary evaporation,and column chromatography to obtain the 1,3 -dicarbonyl compound.

In the above technical solution, the solvent is DMA, DMF, THF, DME ordioxane.

In the above technical solution, the reaction temperature of thereaction is 25 to 60° C.; and the reaction time of the reaction is for0.3 to 2 h.

Generally, to prepare 1,3-dicarbonyl compound 3 from anortho-ester-substituted electron-deficient olefinic compound 1 includestwo methods: the first one is the hydrogen/palladium-carbonhydrogenation reduction of double bond, and then Dieckmann condensationoccurs under basicity. In this process, the use of hydrogen is apotentially dangerous factor, which can cause fire and explosion ifimproperly handled. The second is the direct series reaction with themore expensive Stryker reagent. Therefore, it is of great significanceto use a metal hydride in the Michael-Dieckmann cascade reaction, whichis relatively safe and inexpensive; more importantly, this method usesthe reducibility and alkalinity of sodium hydride, and is very atomiceconomic.

The hydride and palladium compound catalyst of the present invention areeasily available in the laboratory. This method is more convenient, muchhigher in safety. In addition, it is mild in condition but high inreaction yield.

EMBODIMENTS OF THE INVENTION Example 1

Under the protection of nitrogen, palladium chloride (5.3 mg, 0.03 mmol,10 mol %) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) werestirred and suspended in DMA (1.5 mL) for 5 min at 25° C., and then thecompound 1a (0.3 mmol) in DMA (0.5 mL) was added. The reaction wasconducted at 25° C. for 2 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3a with a yield is >99%. The mixture of enol and keto form,enol/keto=16/84. ¹H NMR (400 MHz, CDCl₃): δ 10.37 (br, 1H, enol), 7.78(d, J=7.6 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.53-7.35 (m, 2H), 3.86 (s,3H, enol), 3.79 (s, 3H, keto), 3.74 (dd, J=8.1, 3.9 Hz, 1H, keto), 3.57(dd, J=17.3, 3.4 Hz, 1H, keto), 3.52 (s, 2H, enol), 3.38 (dd, J=17.2,8.2 Hz, 1H, keto). 13C NMR (151 MHz, CDCl3): δ 199.58, 169.68, 153.73,143.33 (enol), 135.61, 135.32 (enol), 129.54 (enol), 127.97, 126.97(enol), 126.68, 124.86, 120.89, 102.30 (enol), 53.27, 52.95, 51.39(enol), 32.65 (enol), 30.40. LR-MS (ESI): m/z 191.2 [M+H]+.

Example 2

Under the protection of nitrogen, palladium acetate (2.7 mg, 0.015 mmol,5 mol %) and lithium hydride (7.2 mg, 0.9 mmol, 3.0 equiv) were stirredand suspended in DMF (1.5 mL) for 5 min at 25° C., and then the compound1a (0.3 mmol) in DMF (0.5 mL) was added. The reaction was conducted at100° C. for 0.3 h. The reaction was quenched by adding a saturatedaqueous ammonium chloride solution. The product was subjected toextraction with ethyl acetate, combining the extract, drying with sodiumsulphate, rotary evaporation, and column chromatography to obtain theproduct 3a with a yield is 91%.

Example 3

Under the protection of nitrogen, Pd₂(dba)₃ (2.7 mg, 0.003 mmol, 1 mol%) and potassium hydride (30% in oil, 200 mg, 1.5 mmol, 5 equiv) werestirred and suspended in THF (1.5 mL) for 5 min at 25° C., and then thecompound 1a (0.3 mmol) in THF (0.5 mL) was added. The reaction wasconducted at 0° C. for 10 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3a with a yield is 82%.

Example 4

Under the protection of nitrogen, Pd(TFA)₂ (100 mg, 0.3 mmol, 100 mol %)and calcium hydride (24 mg, 0.6 mmol, 2.0 equiv) were stirred andsuspended in DME (1.5 mL) for 5 min at 25° C., and then the compound 1a(0.3 mmol) in DME (0.5 mL) was added. The reaction was conducted at 90°C. for 0.3 h. The reaction was quenched by adding a saturated aqueousammonium chloride solution. The product was subjected to extraction withethyl acetate, combining the extract, drying with sodium sulphate,rotary evaporation, and column chromatography to obtain the product 3awith a yield of 83%.

Example 5

Under the protection of nitrogen, [(η³-C₃H₅)PdCl]₂ (2.1 mg, 0.006 mmol,2 mol %) and sodium hydride (60% in oil, 12 mg, 0.30 mmol, 1.0 equiv)were stirred and suspended in dioxane (1.5 mL) for 5 min at 25° C., andthen the compound 1a (0.3 mmol) in dioxane (0.5 mL) was added. Thereaction was conducted at 30° C. for 2 h. The reaction was quenched byadding a saturated aqueous ammonium chloride solution. The product wassubjected to extraction with ethyl acetate, combining the extract,drying with sodium sulphate, rotary evaporation, and columnchromatography to obtain the product 3a with a yield of 65%.

Example 6

Under the protection of nitrogen, Pd(dppp)Cl₂ (18 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) werestirred and suspended in DMA (1.5 mL) for 5 min at 25° C., and then thecompound 1a (0.3 mmol) in DMA (0.5 mL) was added. The reaction wasconducted at 25° C. for 2 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3a with a yield of 63%.

Example 7

Under the protection of nitrogen, Pd(C₆H₅CN)₂Cl₂ (11.4 mg, 0.03 mmol, 10mol %) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) werestirred and suspended in DMA (1.5 mL) for 5 min at 25° C., and then thecompound 1a (0.3 mmol) in DMA (0.5 mL) was added. The reaction wasconducted at 25° C. for 2 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3a with a yield of 77%.

Example 8

Under the protection of nitrogen, Pd(OH)₂ (4.2 mg, 0.03 mmol, 10 mol %)and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were stirredand suspended in DMA (1.5 mL) for 5 min at 25° C., and then the compound1a (0.3 mmol) in DMA (0.5 mL) was added. The reaction was conducted at25° C. for 2 h. The reaction was quenched by adding a saturated aqueousammonium chloride solution. The product was subjected to extraction withethyl acetate, combining the extract, drying with sodium sulphate,rotary evaporation, and column chromatography to obtain the product 3awith a yield of 69%.

Example 9

Under the protection of nitrogen, palladium chloride (5.3 mg, 0.03 mmol,10 mol %) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) werestirred and suspended in DMA (1.5 mL) for 5 min at 25° C., and then thecompound 1b (0.3 mmol) in DMA (0.5 mL) was added. The reaction wasconducted at 25° C. for 2 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3b with a yield of 98%. ¹H NMR (400 MHz, CDCl₃): δ 7.69 (d,J=7.6 Hz, 1H), 7.59-7.40 (m, 6H), 7.38-7.29 (m, 2H), 3.74 (dd, J=8.0,4.3 Hz, 1H), 3.56 (dd, J=16.9, 3.9 Hz, 1H), 3.37 (s, 3H), 3.13 (dd,J=16.8, 8.1 Hz, 1H). ¹³C NMR (151 MHz, CDCl₃): δ 202.19, 169.67, 154.41,143.94, 135.80, 135.10, 129.94, 128.24, 127.95, 127.61, 126.46, 124.42,51.10, 37.92, 31.80. LR-MS (ESI): m/z 266.1 [M+H]+.

Example 10

Under the protection of nitrogen, palladium chloride (5.3 mg, 0.03 mmol,10 mol %) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) werestirred and suspended in DMA (1.5 mL) for 5 min at 25° C., and then thecompound 1c (0.3 mmol) in DMA (0.5 mL) was added. The reaction wasconducted at 25° C. for 2 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3c with a yield of 98%. The mixture of enol and keto form,enol/keto=84/16. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, J=7.6 Hz, 1H,enol), 7.72 (d, J=7.6 Hz, 1H, keto), 7.63-7.46 (m, 2H, enol and keto),7.44-7.33 (m, 1H, enol and keto), 4.11-3.92 (m, 1H, keto), 3.77-3.68 (m,1H, keto), 3.58 (s, 2H, enol), 3.12 (dd, J=17.4, 7.7 Hz, 1H, keto), 2.49(s, 3H, keto), 2.17 (s, 3H, enol). ¹³C NMR (151 MHz, CDCl3): δ 201.52(keto), 199.85 (keto), 191.56, 177.60, 154.24 (keto), 147.63, 138.31,135.52 (keto), 135.14 (keto), 132.88, 127.76 (keto), 127.43, 126.73(keto), 125.85, 124.61 (keto), 123.28, 110.56, 62.07 (keto), 30.38,29.82 (keto), 28.00 (keto), 21.18. LR-MS (ESI): m/z 175.1 [M+H]+.

Example 11

Under the protection of nitrogen, palladium chloride (5.3 mg, 0.03 mmol,10 mol %) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) werestirred and suspended in DMA (1.5 mL) for 5 min at 25° C., and then thecompound 1d (0.3 mmol) in DMA (0.5 mL) was added. The reaction wasconducted at 25° C. for 2 h. The reaction was quenched by adding asaturated aqueous ammonium chloride solution. The product was subjectedto extraction with ethyl acetate, combining the extract, drying withsodium sulphate, rotary evaporation, and column chromatography to obtainthe product 3d with a yield of 99%. The mixture of enol and keto form,enol/keto=87/13. ¹H NMR (400 MHz, CDCl₃): δ 15.08 (br, 1H, enol), 8.14(d, J=7.6 Hz, 2H, keto), 8.00-7.92 (m, 2H, enol), 7.89 (d, J=7.6 Hz, 1H,enol), 7.73 (d, J=7.6 Hz, 1H, keto), 7.62-7.48 (m, 5H, enol and keto),7.44 (t, J=7.2 Hz, 1H, enol), 7.40-7.35 (m, 1H, keto), 4.87 (dd, J=7.4,2.6 Hz, 1H, keto), 3.94 (s, 2H, enol), 3.90-3.75 (m, 1H, keto), 3.34(dd, J=17.1, 7.7 Hz, 1H, keto). ¹³C NMR (151 MHz, CDCl3): δ 200.12(keto), 195.95, 194.40 (keto), 170.91, 154.47 (keto), 148.70, 145.81(keto), 138.03, 136.43 (keto), 135.41 (keto), 134.94 (keto), 133.68(keto), 133.47, 131.40, 129.96, 128.74, 128.25, 127.83 (keto), 127.59,126.65 (keto), 125.73, 124.77(keto), 123.57, 109.58, 56.69 (keto),32.37, 30.20 (keto). LR-MS (ESI): m/z 237.0 [M+H]+.

The invention claimed is:
 1. A method of preparing a 1,3-dicarbonylcompound comprising: under the protection of nitrogen, suspending apalladium compound and a metal hydride in a solvent to form a mixture;adding an electron-deficient olefinic compound to the mixture; stirringthe mixture at 0° C. to 100° C. for 0.3 to 10 hours to obtain the1,3-dicarbonyl compound.
 2. The method according to claim 1, wherein themetal hydride is sodium hydride, lithium hydride, potassium hydride, orcalcium hydride; and the palladium compound is palladium chloride,palladium acetate, Pd₂(dba)₃, Pd(TFA)₂, [(η³-C₃H₅)PdCl]₂, Pd(dppp)Cl₂,Pd(C₆H₅CN)₂Cl₂, or Pd(OH)₂.
 3. The method according to claim 2, whereinthe metal hydride is sodium hydride or lithium hydride; and thepalladium compound is palladium chloride or palladium acetate.
 4. Themethod according to claim 3, wherein the metal hydride is sodiumhydride; and the palladium compound is palladium chloride.
 5. The methodaccording to claim 1, wherein the electron-deficient olefin compound hasthe following structure:

R is an aryl, an alkyl, an alkoxy, or an amino group.
 6. The methodaccording to claim 1, wherein a molar ratio of the palladiumcompound:the metal hydride:the electron-deficient olefin compound is(0.01 to 1):(1 to 5):1.
 7. The method according to claim 6, wherein themolar ratio of the palladium compound:the metal hydride:theelectron-deficient olefin compound is (0.05 to 0.15):(1 to 3):1.
 8. Themethod according to claim 1, further comprising: adding a saturatedammonium chloride aqueous solution to the mixture to quench reaction;and conducting extraction, drying, rotary evaporation, and columnchromatography to obtain the 1,3-dicarbonyl compound.
 9. The methodaccording to claim 1, wherein the solvent is DMA (dimethylacetamide),DMF (dimethylformamide), THF (tetrahydrofuran), DME (dimethoxyethane),or dioxane.
 10. The method according to claim 1, wherein the mixture isstirred at 25 to 60° C. for 0.3 to 2 h.